JP2003055395A - Adenosine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which has an excellent intraocular pressure- lowering action and excellent solubility in water, and is useful as medicines such as a glaucoma medicine or a hypertonia oculi medicine. SOLUTION: A 2-alkynyladenosine 5'-monophosphoric acid represented by the general formula (R is a linear or branched alkyl, a cycloalkyl or a cycloalkyl-substituted alkyl) or its salt, and a medicine containing the same as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 2-alkynyladenosine 5′-monophosphate or a salt thereof which is useful as a therapeutic drug for glaucoma, ocular hypertension and the like, and a medicament containing the same as an active ingredient.

[0002]

2. Description of the Related Art A 2-alkynyladenosine derivative having an alkynyl group at the 2-position of the adenosine skeleton is known to be useful as a therapeutic drug for cardiovascular diseases such as hypertension (Japanese Patent No. 3053908). It is also known that the 2-alkynyladenosine derivative has an excellent effect of lowering intraocular pressure and is useful as a therapeutic drug for eye diseases, particularly for glaucoma and ocular hypertension (WO00 / 120).
98).

However, there has been a problem that 2-alkynyladenosine derivatives, which are conventionally known to have an intraocular pressure lowering action, generally have poor solubility in water. If the solubility in water is poor, it is necessary to add a large amount of a solubilizing agent when preparing a solution such as eye drops, and as a result, there is an unfavorable effect on stability and irritation, and other additives. Often had interactions with each other, and there were restrictions on formulation.

[0004]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide an adenosine derivative having an excellent pharmacological action such as an intraocular pressure lowering action and an excellent solubility in water, and a medicament containing the adenosine derivative as an active ingredient. To provide.

[0005]

In such circumstances, the present inventor has synthesized a large number of various alkynyl adenosine derivatives, and examined their intraocular pressure-lowering effect and solubility in water. Body or salt thereof is reported in WO00 / 12098 2
-Has an intraocular pressure-lowering effect equivalent to that of an alkynyl adenosine derivative and has a much higher solubility in water than those compounds, and thus is particularly useful as a therapeutic agent for glaucoma and ocular hypertension as eye drops. It was found that the present invention has been completed.

That is, the present invention is based on the general formula (1)

[0007]

[Chemical 2]

2-alkynyladenosine 5'-monophosphate represented by the formula: wherein R represents a linear or branched alkyl group which may have a substituent, a cycloalkyl group or a cycloalkyl-substituted alkyl group. Alternatively, the present invention provides a salt thereof and a medicine containing the salt as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-alkynyladenosine 5′-monophosphoric acid or a salt thereof of the present invention is represented by the above-mentioned general formula (1), and in the formula, is a linear or branched chain represented by R. The alkyl group preferably has 1 to 20 carbon atoms, and particularly preferably 1 to 14 carbon atoms. Examples of the linear alkyl group include, for example, methyl group, ethyl group, n-propyl group, n-
Examples thereof include a butyl group, an n-pentyl group, an n-hexyl group, an n-octyl group, an n-decyl group, an n-dodecyl group and an n-tetradecyl group; examples of a branched chain alkyl group include an isopropyl group and an isobutyl group. , T-butyl group, 2-
Examples thereof include an ethylhexyl group. Further, these alkyl groups may have a substituent, and as such a substituent,
Examples thereof include a hydroxyl group, a cyano group and an alkoxy group. The alkoxy group preferably has 1 to 10 carbon atoms. Of these, a linear alkyl group which may be substituted with a cyano group is particularly preferable. The cycloalkyl group represented by R has 3 to 10 carbon atoms, and particularly 3 to 10 carbon atoms.
Examples thereof include a cyclopropyl group, a cyclopentyl group and a cyclohexyl group. The cycloalkyl-substituted alkyl group represented by R, C ₃ -C ₈ cycloalkyl substituted C ₁ -C ₁₀ alkyl group, for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopropylethyl group, cyclopentylethyl group , Cyclohexylethyl group, cyclopropylpropyl group, cyclopentylpropyl group, cyclohexylpropyl group and the like.

Examples of the salt of 2-alkynyladenosine 5'-monophosphoric acid include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; Examples thereof include organic amine salts such as triethylamine salt. Of these, alkali metal salts, particularly sodium salts (monosodium salt, disodium salt) are preferable.

Specific examples of the compound (1) of the present invention include:
The following are mentioned. 2- (1-pentyne-1
-Yl) adenosine 5'-monophosphate or a salt thereof, 2-
(1-Hexyn-1-yl) adenosine 5′-monophosphate or a salt thereof, 2- (1-heptin-1-yl) adenosine 5′-monophosphate or a salt thereof, 2- (1-octin-1-yl) ) Adenosine 5'-monophosphate or a salt thereof,
2- (1-hexadecin-1-yl) adenosine 5'-
Monophosphoric acid or a salt thereof, 2- (3-hydroxy-1-propyn-1-yl) adenosine 5′-monophosphoric acid or a salt thereof, 2- (6-hydroxy-1-hexyn-1-yl) adenosine 5′- Monophosphoric acid or a salt thereof, 2- (3
-Hydroxy-1-octyne-1-yl) adenosine 5'-monophosphate or a salt thereof, 2- (5-cyano-1-
(Pentin-1-yl) adenosine 5'-monophosphate or a salt thereof, 2- (6-cyano-1-hexyn-1-yl)
Adenosine 5'-monophosphate or a salt thereof, 2- (3-methoxy-1-propyn-1-yl) adenosine 5'-monophosphate or a salt thereof, 2- (3-ethoxy-1-propyn-1-yl) Adenosine 5'-monophosphate or a salt thereof, 2- (3-butoxy-1-propyn-1-yl) adenosine 5'-monophosphate or a salt thereof, 2- (4-propoxy-1-butyn-1-yl) Adenosine 5'-monophosphate or a salt thereof, 2- (4-octoxy-1-butyn-1-yl) adenosine 5'-monophosphate or a salt thereof,
2- (5-Ethoxy-1-pentyn-1-yl) adenosine 5′-monophosphate or a salt thereof, 2-cyclobutylethynyladenosine 5′-monophosphate or a salt thereof, 2-cyclopropylethynyladenosine 5′-monoline Acid or salt thereof, 2-cyclopentylethynyl adenosine 5'-
Monophosphoric acid or a salt thereof, 2-cyclohexylethynyl adenosine 5′-monophosphoric acid or a salt thereof, 2- (3-cyclopropyl-1-propyn-1-yl) adenosine 5 ′
-Monophosphoric acid or a salt thereof, 2- (3-cyclopentyl-
1-propyn-1-yl) adenosine 5′-monophosphate or a salt thereof, 2- (3-cyclohexyl-1-propyn-1-yl) adenosine 5′-monophosphate or a salt thereof,
2- (4-cyclopropyl-1-butyn-1-yl) adenosine 5′-monophosphoric acid or a salt thereof, 2- (4-cyclopentyl-1-butyn-1-yl) adenosine 5′-
Monophosphoric acid or its salt, 2- (4-cyclohexyl-1)
-Butyn-1-yl) adenosine 5'-monophosphoric acid or a salt thereof, 2- (5-cyclopropyl-1-pentyn-1)
-Yl) adenosine 5'-monophosphate or a salt thereof

Of these, the following are particularly preferable. 2- (1-octyne-1
-Yl) adenosine 5'-monosodium monophosphate,
2- (1-Octyn-1-yl) adenosine 5′-disodium monophosphate, 2- (1-heptin-1-yl)
Adenosine 5'-monosodium monophosphate, 2- (1
-Heptin-1-yl) adenosine 5'-monophosphate disodium, 2- (6-cyano-1-hexyn-1-yl) adenosine 5'-monophosphate sodium, 2-
(6-Cyano-1-hexyn-1-yl) adenosine 5′-disodium monophosphate

The compound (1) of the present invention can be produced, for example, according to the reaction formula shown below.

[0014]

[Chemical 3]

(Wherein R has the same meaning as described above)

That is, the compound of the present invention is, for example, the Yoshikawa method [Tetrahedron Letters, 50 , 5065-50.
68 (1967)], it can be produced by reacting the compound of the general formula (2) with a phosphoric acid halide. As the solvent, for example, phosphoric acid triesters such as trimethyl phosphate and triethyl phosphate are used, and a mixed solvent of these and water can also be used. Examples of the phosphoric acid halide include phosphoric acid chlorides such as phosphoryl chloride (phosphorus oxychloride). The reaction is -1
It is carried out at 0 to 10 ° C for 0.5 to 6 hours.

In order to isolate the desired product from the reaction mixture, it is preferable to convert it into a phosphoric acid compound or a salt of a phosphoric acid compound by a neutralization reaction, a salt formation reaction or the like. By appropriately combining these neutralization reaction and salt formation reaction, a highly pure target product can be obtained. It is preferable that the reaction mixture is reacted with an organic amine to be isolated as an organic amine salt, neutralized if necessary, and further converted to another salt if necessary. In order to isolate the desired product as an organic amine salt, for example, chromatography using an organic amine solution as an eluent is preferable. A phosphoric acid body can be produced by reacting the obtained organic amine salt in water in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid at -10 to 10 ° C.

Further, salts of other phosphoric acid compounds can be produced by using a commonly known salt forming reaction. That is, in the case of the alkali metal salt, the phosphoric acid body, methanol,
Produced by reacting at 0 ° C. to room temperature in an alcohol such as ethanol, N, N-dimethylformamide, water or a mixed solvent thereof in the presence of an alkali metal compound such as lithium hydroxide, sodium hydroxide or potassium hydroxide. can do. The salt of such a phosphoric acid body is particularly preferable because it has high solubility in water.

Since the compound (1) of the present invention thus obtained has an excellent action of lowering intraocular pressure and has excellent solubility in water, it can be used as a drug such as a therapeutic drug for glaucoma and ocular hypertension. It is useful. The medicament of the present invention is mainly administered parenterally, but it can also be administered orally.
Examples of the parenteral administration agent include eye drops, eye ointments, injections and the like, and eye drops are particularly preferable. Examples of the orally-administered agent include solid preparations such as powder, granules, capsules and tablets. These formulations can be produced by a conventional method by adding a pharmaceutically acceptable formulation additive and the like to the compound of the present invention.

For example, when an eye drop is prepared, an isotonic agent such as sodium chloride or glycerin; a stabilizer such as sodium edetate; a benzalkonium chloride or a paraben, if necessary, to the compound of the present invention. Preservatives such as; sodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid, sodium tetraborate (borax), hydrochloric acid, sodium hydroxide, etc. Good. Since the compound of the present invention has high solubility in water, it does not require a solubilizing agent for formulation,
It has excellent stability and is free from problems such as irritation, and is particularly excellent for use as an eye drop.

When preparing an injectable preparation, the compound of the present invention is added to the compound of the present invention, if necessary, such as hydrochloric acid, sodium hydroxide, sodium hydrogen phosphate, sodium dihydrogen phosphate, etc .;
It is also dissolved in distilled water for injection with an isotonicity agent such as sodium chloride, aseptically filtered and filled in an ampoule, or mannitol, gelatin, etc. are further added and freeze-dried under vacuum to prepare a dissolution type injection before use. Good.

When preparing a solid preparation for oral administration, an excipient such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, etc. may be added to the compound of the present invention, if necessary; sucrose, hydroxypropyl cellulose, polyvinyl. A binder such as pyrrolidone; a disintegrating agent such as carmellose calcium; a lubricant such as magnesium stearate and talc may be mixed and formulated by a conventional method. Further, these solid preparations can be coated with an enteric base such as hydroxypropylmethylcellulose phthalate or methacrylic acid / methyl methacrylate copolymer to prepare an enteric preparation.

The dose of the adenosine derivative (1), which is the active ingredient of the medicament of the present invention, is appropriately selected according to the age, weight, pathological condition, dosage form of the patient, etc.
It is preferable to apply or apply 001 to 10% (w / v) once or several times a day. Oral preparations or injections usually take 0.001 to 1000 mg once a day or It is preferable to administer in several divided doses.

[0024]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 2- (1-Octyn-1-yl) adenosine 5'-monophosphate triethylamine salt: 2-
(1-Octyn-1-yl) adenosine 1.13 g was dissolved in triethyl phosphate (20 mL), phosphorus oxychloride (1.09 mL, 3.9 eq.) Was added under ice cooling, and the mixture was stirred at the same temperature for 5 hours. . The reaction mixture was neutralized (pH 8) with saturated aqueous sodium carbonate solution (45 mL), and then washed with ether. After the ether in the aqueous layer was distilled off under reduced pressure, the residue was purified by C ₁₈ silica gel column chromatography (0.1M triethylammonium acetate buffer: acetonitrile = 100: 0 to 60:40), and then the concentrated fraction was collected. C ₁₈ silica gel column chromatography (water: acetonitrile = 10
The triethylammonium acetate buffer solution was removed at 0: 0 to 40:60) and the residue was lyophilized to obtain 853 mg of the title compound as a pale yellow amorphous substance. ¹ H-NMR (D ₂ O) δ: 0.67 (t, 3H, J = 6.8Hz), 1.09 (t,
9H, J = 7.3Hz), 1.06-1.30 (m, 6H), 1.41 (tt, 2H, J =
6.8Hz, 7.1Hz), 2.25 (t, 2H, J = 7.0Hz), 3.00 (q, 6
H, J = 7.3Hz), 3.92-3.96 (m, 2H), 4.17-4.21 (m, 1
H), 4.31 (dd, 1H, J = 3.9Hz, 5.1Hz), 4.51 (dd, 1H,
J = 5.1Hz, 5.3Hz), 5.89 (d, 1H, J = 5.3Hz), 8.28
(S, 1H). ³¹ P-NMR (D ₂ O) δ: 0.78 (s). IR (KBr) ν _max : 3328, 3172, 2934, 2491, 2239, 164
6, 1591, 1457, 1381, 1227, 1171, 1067, 922, 797, 7
23 cm ^-1 _.

Example 2 2- (1-Heptin-1-yl) adenosine 5'-monophosphate triethylamine salt: Using the same method as in Example 1, 2- (1-heptin-1-yl) adenosine ( 2.
From 53 g), 641 mg of the title compound was obtained as a colorless amorphous. ¹ H-NMR (D ₂ O) δ: 0.86 (t, 3H, J = 7.1Hz), 1.23 (t,
9H, J = 7.3Hz), 1.29-1.44 (m, 4H), 1.59 (tt, 2H, J =
7.0Hz, 7.2Hz), 2.41 (t, 2H, J = 7.0Hz), 3.15 (q, 6
H, J = 7.3Hz), 4.06-4.14 (m, 2H), 4.32-4.36 (m, 1
H), 4.45 (dd, 1H, J = 3.9Hz, 5.1Hz), 4.65 (dd, 1H,
J = 5.1Hz, 5.3Hz), 6.03 (d, 1H, J = 5.3Hz), 8.42
(S, 1H). ³¹ P-NMR (D ₂ O) δ: 10.25 (s). IR (KBr) ν _max : 3337, 3181, 2935, 2676, 2491, 223
8, 1654, 1593, 1457, 1227, 1171, 1066, 924, 796, 7
23 cm ^-1 .

Example 3 2- (6-Cyano-1-hexyn-1-yl) adenosine 5'-monophosphate triethylamine salt: Using the same method as in Example 1, 2- (6-cyano-1- Hexin-1-yl) adenosine (2.41 g) to give the title compound (1.14 g)
Was obtained as a colorless amorphous. ¹ H-NMR (D ₂ O) δ: 1.10 (t, 9H, J = 7.3Hz), 1.57-1.74
(M, 4H), 2.34-2.42 (m, 4H), 3.02 (q, 6H, J = 7.3H
z), 3.91-4.03 (m, 2H), 4.20-4.22 (m, 1H), 4.32
(Dd, 1H, J = 4.4Hz, 4.9Hz), 4.52 (dd, 1H, J = 4.9Hz,
5.3Hz), 5.89 (d, 1H, J = 5.3Hz), 8.28 (s, 1H). ³¹ P-NMR (D ₂ O) δ: -2.25 (s). IR (KBr) ν _max : 3337, 3179, 2938, 2678, 2243, 165
4, 1637, 1594, 1457, 1380, 1068, 919cm ^-1 .

Example 4 2- (1-Octyn-1-yl) adenosine 5'-monophosphate: 2- (1-Octyn-1-yl) adenosine 5'-monophosphate triethylamine salt (279 mg) was added to water (4
mL), 1N hydrochloric acid (1 mL) was added under ice cooling, and the mixture was allowed to stand for 10 minutes. After diluting with water (10 mL), filter and wash with water (5 m
L), ethanol twice (5 mL each), ether twice (5 mL)
Each) to give 213 mg of the title compound as a pale yellow amorphous. ¹ H-NMR (D ₂ O + NaOD) δ: 0.84 (t, 3H, J = 6.4Hz) 1.23-
1.42 (m, 6H), 1.46-1.55 (m, 2H), 2.37 (t, 2H, J =
6.8Hz), 3.90-4.12 (m, 4H), 4.48 (dd, 1H, J = 4.9H
z, 5.9Hz), 5.86 (d, 1H, J = 5.9Hz), 8.31 (s, 1
H). ³¹ P-NMR (D ₂ O + NaOD) δ: 4.01 (s). IR (KBr) ν _max : 3329, 3127, 2931, 2239, 1688, 159
1, 1509, 1458, 1387, 1329, 1219, 1085, 955, 779, 7
22cm ^-1 _.

Example 5 2- (1-heptin-1-yl) adenosine 5'-monophosphate: Using the same method as in Example 4, 2- (1-
The title compound (408 mg) was obtained as a colorless amorphous form from heptyn-1-yl) adenosine 5′-monophosphate triethylamine salt (597 mg). ¹ H-NMR (D ₂ O + NaOD) δ: 0.83 (t, 3H, J = 7.2Hz), 1.21
-1.42 (m, 4H), 1.57 (tt, 2H, J = 7.0Hz, 7.4Hz), 2.3
9 (t, 2H, J = 7.0Hz), 3.86-3.96 (m, 2H), 4.19-4.23
(M, 2H), 4.59 (dd, 1H, J = 3.4Hz, 5.5Hz), 5.86
(D, 1H, J = 5.5Hz), 8.50 (s, 1H). ³¹ P-NMR (D ₂ O + NaOD) δ: 13.8 (s). IR (KBr) ν _max : 3320, 3126, 2933, 2238, 1686, 159
1, 1509, 1458, 1388, 1330, 1219, 1082, 958, 781, 7
22 cm ^-1 _.

Example 6 2- (6-Cyano-1-hexyn-1-yl) adenosine 5'-monophosphate: Using the same method as in Example 4, 2- (6-cyano-1-hexyne- 1-yl) adenosine 5'-monophosphate triethylamine salt (1.1 g)
The title compound (617 mg) was obtained as a colorless amorphous. ¹ H-NMR (D ₂ O + NaOD) δ: 1.59-1.75 (m, 4H), 2.36-2.
42 (m, 4H), 3.44-3.51 (m, 2H), 4.09-4.10 (m, 1
H), 4.49 (dd, 1H, J = 4.4Hz, 4.9Hz), 4.65 (dd, 1H,
J = 4.9Hz, 5.5Hz), 5.73 (d, 1H, J = 5.5Hz), 8.41 (s,
1H). ³¹ P-NMR (D ₂ O + NaOD) δ: 1.44 (s). IR (KBr) ν _max : 3330, 3125, 2934, 2241, 1690, 159
2, 1398, 1227, 1081, 967cm ^-1 _.

Example 7 2- (1-Octyn-1-yl) adenosine 5'-monophosphate monosodium and 2- (1-octyne-1)
-Yl) adenosine 5'-monophosphate disodium: 2- (1-octin-1-yl) adenosine 5'-monophosphate (3.87 g) was suspended in water (20 mL), and a 1N aqueous sodium hydroxide solution (8.5 (mL) was added and stirred for 5 hours. After diluting with water (5 mL), it was purified by C ₁₈ silica gel column chromatography (water: acetonitrile = 100: 0 to 20:80), and the residue was lyophilized to give 2- (1
-Octyn-1-yl) adenosine 5'-monophosphate
712 mg of monosodium as pale yellow amorphous, 2
1.73 g of-(1-octin-1-yl) adenosine 5'-disodium monophosphate was obtained as a pale yellow amorphous substance.

7a: 2- (1-Octyn-1-yl) adenosine 5'-monophosphate monosodium MS (ESI-) m / z: 454 (M ⁺ ) -H-Na. ¹ H-NMR (D ₂ O) δ: 0.64 (t, 3H, J = 6.6Hz) 1.02-1.09
(M, 4H), 1.04-1.23 (m, 2H), 1.33-1.42 (m, 2H),
2.21 (t, 2H, J = 7.1Hz), 3.87-3.97 (m, 2H), 4.19-4.
23 (m, 1H), 4.28 (dd, 1H, J = 4.3Hz, 4.7Hz), 4.46
(Dd, 1H, J = 4.7Hz, 5.0Hz), 5.85 (d, 1H, J = 5.0Hz),
8.22 (s, 1H). ³¹ P-NMR (D ₂ O) δ: 0.96 (s). IR (KBr) ν _max : 3369, 3189, 2931, 2240, 1640, 159
_{. 0, 1450, 1385, 1267} , 1213, 1069, 917cm -1 UV (H 2 O) λ max:. 270, 233nm 7b: 2- (1- octyne-1-yl) adenosine
5'-Monophosphoric acid disodium salt MS (ESI-) m / z: 454 (M ⁺ ) -H-2Na. ¹ H-NMR (D ₂ O) δ: 0.70 (t, 3H, J = 7.2Hz) 1.10 -1.15
(M, 4H), 1.24-1.33 (m, 2H), 1.41-1.50 (m, 2H),
2.29 (t, 2H, J = 7.2Hz), 3.82-3.84 (m, 2H), 4.17-4.
21 (m, 1H), 4.33 (dd, 1H, J = 3.6Hz, 4.9Hz), 4.59
(Dd, 1H, J = 4.9Hz, 5.9Hz), 5.91 (d, 1H, J = 5.9Hz),
8.45 (s, 1H). ³¹ P-NMR (D ₂ O) δ: 3.67 (s). IR (KBr) ν _max : 3328, 3189, 2931, 2237, 1646, 158
_{. 5, 1450, 1384, 1268} , 1214, 1091, 979cm -1 UV (H 2 O) λ max: 270, 233nm.

Example 8 2- (1-Heptin-1-yl) adenosine 5'-monophosphate monosodium and 2- (1-heptin-1)
-Yl) adenosine 5'-disodium monophosphate:
Using the same method as in Example 7, 2- (1-heptin-
1-yl) adenosine 5'-monophosphate (530 mg) to 2- (1-heptin-1-yl) adenosine 5'-monophosphate monosodium 203 mg as colorless amorphous, 2- (1-heptin-1-yl) Adenosine 5 '
-323 mg of disodium monophosphate was obtained as a colorless amorphous.

8a: 2- (1-heptin-1-yl) adenosine 5'-monophosphate monosodium MS (ESI-) m / z: 440 (M ⁺ ) -H-Na. ¹ H-NMR (D ₂ O) δ: 0.73 (t, 3H, J = 7.2Hz), 1.09-1.33
(M, 4H), 1.42-1.51 (m, 2H), 2.29 (t, 2H, J = 7.0H
z), 3.95-4.00 (m, 2H), 4.20-4.24 (m, 1H), 4.32
(Dd, 1H, J = 3.8Hz, 5.2Hz), 4.53 (dd, 1H, J = 5.2Hz,
5.3Hz), 5.91 (d, 1H, J = 5.3Hz), 8.30 (s, 1H). ³¹ P-NMR (D ₂ O) δ: 3.22 (s). IR (KBr) ν _max : 3840, 3179, 2934, 2678, 2238, 163
8, 1592, 1457, 1381, 1267, 1217, 1178, 1085, 923,
797, 723cm ^-1 UV (H ₂ O) λ _max : 270, 233nm. 8b: 2- (1-heptin-1-yl) adenosine
5'-Disodium monophosphate MS (ESI-) m / z: 440 (M ⁺ ) -H-2Na. ¹ H-NMR (D ₂ O) δ: 0.74 (t, 3H, J = 7.0Hz), 1.13 -1.34
(M, 4H), 1.44-1.53 (m, 2H), 2.31 (t, 2H, J = 7.2H
z), 3.82-3.87 (m, 2H), 4.19-4.22 (m, 1H), 4.32-
4.39 (m, 1H), 4.59-4.63 (m, 1H), 5.93 (d, 1H, J =
5.8Hz), 8.47 (s, 1H). ³¹ P-NMR (D ₂ O) δ: 3.79 (s). IR (KBr) ν _max : 3422, 3181, 2932, 2237, 1685, 159
0, 1458, 1438, 1387, 1340, 1269, 1227, 1090, 979,
795, 721cm ^-1 UV (H ₂ O) λ _max : 270, 233nm.

Example 9 2- (6-Cyano-1-hexyn-1-yl) adenosine 5'-monophosphate Monosodium and 2- (6-cyano-1-hexyn-1-yl) adenosine 5'-monoline Disodium acid salt: 2- (6-Cyano-1-hexyn-1-yl) adenosine 5'-monophosphate (800 mg) was used in the same manner as in Example 7 to give 2- (6-cyano-1- Hexin-1-yl) adenosine 5′-monophosphate monosodium 130 mg was obtained as colorless amorphous, and 2- (6-cyano-1-hexyn-1-yl) adenosine 5′-monophosphate disodium 709 mg was obtained as colorless amorphous. .

9a: 2- (6-cyano-1-hexyne-
1-yl) adenosine 5'-monophosphate monosodium MS (ESI-) m / z: 451 (M ⁺ ) -H-Na. ¹ H-NMR (D ₂ O) δ: 1.60-1.76 (m, 4H) , 2.37-2.46 (m,
4H), 3.95-4.09 (m, 2H), 4.23-4.26 (m, 1H), 4.3
5 (dd, 1H, J = 4.2Hz, 4.9Hz), 4.55 (dd, 1H, J = 4.9H
z, 5.3Hz), 5.92 (d, 1H, J = 5.3Hz), 8.31 (s, 1
H). ³¹ P-NMR (D ₂ O) δ: 0.56 (s). IR (KBr) ν _max : 3338, 3190, 2942, 2244, 1647, 159
4, 1383, 1070, 923 cm ^-1 UV (H ₂ O) λ _max : 270, 232 nm. 9b: 2- (6-cyano-1-hexyn-1-yl) adenosine 5'-monophosphate disodium MS (ESI -) M / z: 451 (M ⁺ ) -H-2Na. ¹ H-NMR (D ₂ O) δ: 1.58-1.77 (m, 4H), 2.38-2.45 (m,
4H), 3.86-3.88 (m, 2H), 4.20-4.25 (m, 1H), 4.3
6 (dd, 1H, J = 4.2Hz, 4.9Hz), 4.62 (dd, 1H, J = 4.9H
z, 5.5Hz), 5.94 (d, 1H, J = 5.5Hz), 8.48 (s, 1
H). ³¹ P-NMR (D ₂ O) δ: 1.33 (s). IR (KBr) ν _max : 3368, 2244, 1654, 1593, 1368, 108
9,978cm ^-1 UV (H ₂ O) λ _max : 270, 232nm.

The compounds used in the following test examples are as follows. Inventive Compound 1: 2- (1-Heptin-1-yl) adenosine 5′-Disodium monophosphate (Compound of Example 8b) Inventive Compound 2: 2- (6-Cyano-1-hexyne-1)
-Yl) adenosine 5'-disodium monophosphate (compound of Example 9b) Invention compound 3: 2- (1-octin-1-yl) adenosine 5'-monosodium monophosphate (compound of Example 7a) Reference Compound 1: 2- (1-heptin-1-yl) adenosine (compound described in Patent No. 3053908) Reference compound 2: 2- (1-octin-1-yl) adenosine (compound described in WO00 / 12098)

Test Example 1 A borate buffer solution (pH) containing polysorbate 80 was prepared so that the test compound was a 0.1 or 1.0% (W / V) concentration solution.
It was dissolved in 7.0). In the test, intraocular pressure was measured using a Japanese white male rabbit (Kitayama Labes) having a body weight of 2.7 to 3.9 kg. Rabbits were retained by a box-type retainer before use. Intraocular pressure is measured by Mentor Model 30 Classic Pne
It was measured under anesthesia using a umatonometer. Prior to the intraocular pressure measurement, surface anesthesia of the cornea was performed by instillation of 0.4% oxybuprocaine hydrochloride (Benoxir 0.4% ophthalmic solution, manufactured by Santen Pharmaceutical Co., Ltd.). The intraocular pressure was measured several times at regular intervals, and the average value of three intraocular pressures that became constant was taken.
50 μL of each test compound solution was instilled into one eye, and at the same time, 50 μL of the eye drop base was instilled into the opposite eye. The intraocular pressure was measured 60 minutes before instillation of the test compound, 0 minutes immediately before instillation of the test compound, 30, 60, 90, 1 after instillation of the test compound.
20, 150, 180, 240, 300, 360, 42
The intraocular pressure of both eyes was measured with time at 0 and 480 minutes. Each experiment was carried out using 3 to 6 rabbits. As a control, eye drops were applied to both eyes and the intraocular pressure was measured in the same manner.
The intraocular pressure-lowering effect is, for each group, "change in intraocular pressure difference between eyes instilled with test compound and eye with instilled base-area under time curve" (hereinafter, abbreviated as AUC (mmHg · min)) and " Evaluation was performed using "the maximum change value of the intraocular pressure difference between the eye instilled with the test compound and the eye instilled with the eyedrop base" (hereinafter, abbreviated as E _max (mmHg)) as an index. Table 1 shows the AUC and E _max of the test compound.

[0039]

[Table 1]

Test Example 2 A test compound was suspended in an isotonic borate buffer solution having a pH of 7.0,
After shaking at 20 ° C. for 6 hours, centrifugation was performed and the concentration of the test compound in the supernatant was measured by high performance liquid chromatography.
The saturated solubility was determined. The results are shown in Table 2. (Measurement conditions) Detector: Ultraviolet absorptiometer (wavelength: 270 nm) Column: ODS column with inner diameter 4.6 mm, length 15 cm Mobile phase: Acetonitrile / triethylamine acetic acid buffer (pH 7) mixture flow rate: 0.7 mL / min

[0041]

[Table 2]

From the results shown in Table 1, the compound of the present invention has an excellent action of lowering intraocular pressure, and from the results shown in Table 2, the compound of the present invention has excellent solubility in water. It also satisfied both the effect of lowering intraocular pressure and the solubility in water.

Example 10 (eye drops) Compound of the present invention 3 0.1 g Boric acid 1.19 g Borax (decahydrate) 0.08 g Sodium chloride 0.27 g Benzalkonium chloride 5 mg Sterile purified water Appropriate amount 100 mL total The prescription ophthalmic solution was prepared, and after sterile filtration, 5 mL each was filled in a polypropylene ophthalmic container.

Example 11 (Injection) Inventive compound 3 0.5 g Sodium chloride 9 g Water for injection Appropriate amount 1000 mL An injection of the above formulation was prepared, sterile filtered, and filled in glass ampoules at 2 mL each.

Example 12 (oral preparation) Compound 3 of the present invention 5 mg Lactose 93 mg Potato starch 30 mg Crystalline cellulose 15 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 2 mg Total amount 150 mg (in one tablet) In accordance with the above formulation, the compound of the present invention 3, lactose, potato Starch, crystalline cellulose and hydroxypropyl cellulose were mixed, water was added and kneaded, and extruded with a screen to granulate. After the granules were dried, magnesium stearate was added and tablets were made.

[0046]

INDUSTRIAL APPLICABILITY The compound of the present invention is excellent not only in the action of lowering intraocular pressure but also in solubility in water, and is useful as a drug such as a therapeutic agent for glaucoma and ocular hypertension.
Even when it is used as a water-soluble liquid, it is not necessary to add a solubilizing agent or the like or heat treatment, and the quality and stability are improved. In particular, it is suitable as a water-soluble drug such as eye drops and injections.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kazuhiro Uemoto             2-293-3 Amanuma, Saitama City, Saitama Prefecture             ー Inside Tokyo Research Center, AEIYO Co., Ltd. (72) Inventor Shinya Onuma             2-293-3 Amanuma, Saitama City, Saitama Prefecture             ー Inside Tokyo Research Center, AEIYO Co., Ltd. (72) Inventor Yoshikazu Kato             1 Tanaka, Yuno, Iinosaka-cho, Fukushima City, Fukushima Prefecture             ー Inside Aiyo Co., Ltd. Fukushima Laboratory F-term (reference) 4C057 AA17 BB02 CC03 DD01 LL33                       LL41 LL44                 4C086 AA01 AA02 AA03 EA18 MA01                       MA04 MA58 NA14 ZA33

Claims (5)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R represents a linear or branched alkyl group which may have a substituent, a cycloalkyl group or a cycloalkyl-substituted alkyl group), and 2-alkynyladenosine 5'-monophosphate or a salt thereof. . 2. 2- (1-Octyn-1-yl) adenosine 5'-monophosphate monosodium, 2- (1-octin-1-yl) adenosine 5'-monophosphate disodium, 2- (1- Heptin-1-yl) adenosine 5 '
-Monosodium monophosphate, 2- (1-heptin-1
-Yl) adenosine 5'-disodium monophosphate, 2
-(6-Cyano-1-hexyn-1-yl) adenosine 5'-monophosphate monosodium or 2- (6-cyano-1-hexyn-1-yl) adenosine 5'-monophosphate disodium Item 2-Alkynyladenosine 5′-monophosphoric acid or a salt thereof according to item 1. 3. A medicine comprising the 2-alkynyladenosine 5′-monophosphoric acid or a salt thereof according to claim 1 or 2 as an active ingredient. 4. The medicine according to claim 3, which is a therapeutic drug for glaucoma and ocular hypertension. 5. The medicine according to claim 3, which is an eye drop.